Abstract: Atherosclerosis is the primary cause of heart attack and stroke, which account for approximately 50% of all deaths and is the leading cause of disability in the US. There are no effective therapy and medicine for this disease. RNA interference (RNAi), mediated by small interfering RNA (siRNA), silences genes with a high degree of specificity and represents a potential targeted molecular therapy. We have recently identified Rcn2 gene as a major atherosclerosis susceptibility locus affecting both early and advanced lesion formation in mice. Rcn2 knockout mice showed significantly smaller atherosclerosis lesions compared to background mice. Knockdown of Rcn2 in vitro with small interfering RNAs resulted in significant reductions in both baseline and oxidized phospholipid-induced vascular cell adhesion molecule (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) expression by endothelial cells, both of which play important role in the development of atherosclerosis. We therefore hypothesize that silencing this Rcn2 gene with siRNAs will result in effective therapy for atherosclerosis in mouse model. However, because naked siRNA is subject to degradation by enzyme in vivo, has large molecular weight and possesses strong anionic charges, an effective carrier system is required to escort and facilitate the access of siRNA to its intracellular target of action. As endogenous nanoparticles (at 40nm-100nm) composed with lipid layers similar to liposome but with abundance of proteins, exosomes emerge as promising clinically suitable, safe and effective vehicles for siRNA delivery because of its immunological inertness, possible intrinsic targeting capability to the origin cells from which they are derived, and flexible chemical membrane modifications and interior space to introduce targeting, diagnostic or therapeutic multiple function features. Thus, we explore the concept of using exosomes generated from endothelial cells to systemically deliver siRNA against Rcn2 gene in genetic mouse model. Highly quantitative positron emission tomography (PET) will be employed as real-time tracing tool to evaluate and design the exosome for siRNA delivery. The success of this project will provide not only a novel strategy of RNAi therapy for the prevention and treatment of atherosclerosis, but also the PET imaging techniques that are able to quantitatively reveal the dynamics of the nanocarrier in living system and are potential to have broad impact on the development of exosome-based delivery system for many other human diseases.